T<scp>ranslational</scp> A<scp>dvances</scp> <scp>in</scp> <scp>the</scp> F<scp>ield</scp> <scp>of</scp> P<scp>ulmonary</scp> H<scp>ypertension</scp> Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing

Austin, Eric D.; West, James; Loyd, James E.; Hemnes, Anna R.

doi:10.1164/rccm.201605-0905pp

Cited by 34 publications

(31 citation statements)

References 78 publications

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“…Many diverse and wideranging studies have further increased our knowledge, which include examples of studies involving epidemiologic data from patient registries (17,(19)(20)(21)(22); diagnostic strategies, including the role of cardiac catheterization and AVT (23,24); insights into the genetics and molecular strategies for precision medicine in PAH (25)(26)(27); and pediatric-specific approaches toward monitoring disease progression with novel endpoints (28)(29)(30) and interventions (31). More recently, others have formed teams to make recommendations for care guidelines, such as those recently published by European investigators (32).…”

Section: Recent Advances In Pediatric Pulmonary Hypertensionmentioning

confidence: 99%

Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension

Ivy

Archer

Wilson

2016

Am J Respir Crit Care Med

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Although pulmonary hypertension (PH) contributes significantly to poor outcomes in diverse pediatric diseases, approaches toward the care of children with PH have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a committee of experienced clinicians was formed to systematically identify, synthesize, and appraise relevant evidence and then to formulate evidence-based recommendations regarding the diagnosis and management of pediatric PH. This brief report is an executive summary of the officially approved guidelines developed by the committee, highlighting a few key recommendations regarding the care of children with PH. Guidelines and the rationale for grading the strength of each recommendation are included in the online supplement.

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Section: Recent Advances In Pediatric Pulmonary Hypertensionmentioning

confidence: 99%

Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension

Ivy

Archer

Wilson

2016

Am J Respir Crit Care Med

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“…The goal of personalised medicine is to streamline clinical decision to provide the right treatment strategy for a given patient based on his or her individual characteristics (figure 1) [3]. It consists of classifying each patient into a subpopulation, taking into account their susceptibility to develop a particular disease or phenotype and its response to a treatment.…”

Section: How Could Precision Medicine Add To Current Pah/ph Management?mentioning

confidence: 99%

“…Gene editing and gene therapy are promising emerging technologies that could correct pathogenic mutations in patients with heritable PAH [3]. Using an adenovirus vector, REYNOLDS et al [84] showed that BMPR2 gene delivery could restore BMPR-II expression, improve haemodynamics and attenuate vascular remodelling in monocrotaline-induced and chronic-hypoxia models of PH in rats.…”

Section: Is Precision Medicine Ready For Use In Pah/ph?mentioning

confidence: 99%

Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era

et al. 2018

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Pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) include different cardiopulmonary disorders in which the interaction of multiple genes with environmental and behavioural factors modulates the onset and the progression of these severe conditions. Although the development of therapeutic agents that modulate abnormalities in three major pathobiological pathways for PAH has revolutionised our approach to the treatment of PAH, the long-term survival rate remains unsatisfactory. Accumulating evidence has underlined that clinical outcomes and responses to therapy in PAH are modified by multiple factors, including genetic variations, which will be different for each individual. Since precision medicine, also known as stratified medicine or personalised medicine, aims to better target intervention to the individual while maximising benefit and minimising harm, it has significant potential advantages. This article aims to assemble and discuss the different initiatives that are currently underway in the PH/PAH fields together with the opportunities and prospects for their use in the near future.

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“…In addition, variants in endostatin ( Col18a1 ) and the endothelin‐1 pathway gene GNG2 are associated with clinical outcomes in PAH and may influence the response to treatment. Studies in large populations of IPAH/HPAH patients are underway, such as the UK National Institute of Health Research Biomedical Research Centres Inherited Diseases Genetic Evaluation (BRIDGE) consortium and US National Biological Sample and Data Repository for PAH, to assess the prevalence of both common and rare variants in PAH .…”

Section: Introductionmentioning

confidence: 99%

Pulmonary arterial hypertension – progress in understanding the disease and prioritizing strategies for drug development

et al. 2017

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Abstract. Ghataorhe P, Rhodes CJ, Harbaum L, Attard M, Wharton J, Wilkins MR (Imperial College London, London, UK). Pulmonary arterial hypertensionprogress in understanding the disease and prioritizing strategies for drug development (Review). J Intern Med 2017; 282: 129-141.Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease. The breadth and depth of expertise focused on unravelling the molecular pathology of PAH has yielded novel insights, including the role of growth factors, inflammation and metabolic remodelling. The description of the genetic architecture of PAH is accelerating in parallel, with novel variants, such as those reported in potassium two-pore domain channel subfamily K member 3 (KCNK3), adding to the list of more established mutations in genes associated with bone morphogenetic protein receptor type 2 (BMPR2) signalling. These insights have supported a paradigm shift in treatment strategies away from simply addressing the imbalance of vasoactive mediators observed in PAH towards tackling more directly the structural remodelling of the pulmonary vasculature. Here, we summarize the changing clinical and molecular landscape of PAH. We highlight novel drug therapies that are in various stages of clinical development, targeting for example cell proliferation, metabolic, inflammatory/immune and BMPR2 dysfunction, and the challenges around developing these treatments. We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both as potential drug targets and as biomarkers for patient selection. The expectation is that together these will enable the prioritization of potential therapies in development and the evolution of personalized medicine for PAH.

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Translational Advances in the Field of Pulmonary Hypertension Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing

Cited by 34 publications

References 78 publications

Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension

Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension

Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era

Pulmonary arterial hypertension – progress in understanding the disease and prioritizing strategies for drug development

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